Related Experiment Video
Updated: Jun 26, 2026
A Murine Model of Dengue Virus-induced Acute Viral Encephalitis-like Disease
Published on: April 28, 2019
SARS-CoV-2 Spike Protein Exacerbates Thromboembolic Cerebrovascular Complications in Humanized ACE2 Mouse Model
Stan P Heath1, Veronica C Hermanns1, Maha Coucha2
1Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA, USA.
Insights
The SARS-CoV-2 spike protein worsens stroke by disrupting the renin-angiotensin-aldosterone system (RAAS), increasing blood clots, and reducing clot breakdown. Losartan treatment reversed these effects, highlighting a potential therapeutic target for COVID-19-related cerebrovascular complications.
Area of Science:
- Neuroscience
- Cardiovascular Biology
- Infectious Disease
Background:
- COVID-19 is linked to increased risk of acute ischemic stroke.
- The precise molecular mechanisms underlying this association remain unclear.
- The SARS-CoV-2 spike protein's role in exacerbating stroke and cerebrovascular complications is a critical area of investigation.
Purpose of the Study:
- To investigate the hypothesis that SARS-CoV-2 spike protein increases coagulation and decreases fibrinolysis by disrupting the renin-angiotensin-aldosterone system (RAAS).
- To evaluate the therapeutic potential of Losartan, an angiotensin receptor (AT1R) blocker, in mitigating spike protein-induced cerebrovascular damage.
Main Methods:
- A thromboembolic stroke model was induced in humanized ACE2 knock-in mice after SARS-CoV-2 spike protein injection.
- Mice were treated with Losartan, and outcomes including cerebral blood flow, infarct size, and cognitive function were assessed.
- Human brain microvascular endothelial cells (HBMEC) were exposed to hypoxia with/without spike protein to analyze inflammation, RAAS balance, coagulation, and fibrinolysis.
Main Results:
- SARS-CoV-2 spike protein induced RAAS imbalance, increased inflammation, and promoted hypercoagulation while decreasing fibrinolysis.
- These effects correlated with reduced cerebral blood flow, increased neuronal death, and impaired cognitive function.
- Losartan treatment effectively restored RAAS balance and ameliorated spike protein-induced neurovascular damage and cognitive decline.
Conclusions:
- SARS-CoV-2 spike protein exacerbates inflammation and hypercoagulation, contributing to neurovascular damage and cognitive dysfunction.
- Disruption of the RAAS by the spike protein is a key mechanism driving these complications.
- Targeting the AT1R with Losartan demonstrates a promising therapeutic strategy for managing COVID-19-associated thromboembolic cerebrovascular events.
Abstract:
COVID-19 increases the risk for acute ischemic stroke, yet the molecular mechanisms are unclear and remain unresolved medical challenges. We hypothesize that the SARS-CoV-2 spike protein exacerbates stroke and cerebrovascular complications by increasing coagulation and decreasing fibrinolysis by disrupting the renin-angiotensin-aldosterone system (RAAS). A thromboembolic model was induced in humanized ACE2 knock-in mice after one week of SARS-CoV-2 spike protein injection. hACE2 mice were treated with Losartan, an angiotensin receptor (AT1R) blocker, immediately after spike protein injection. Cerebral blood flow and infarct size were compared between groups. Vascular-contributes to cognitive impairments and dementia was assessed using a Novel object recognition test. Tissue factor-III and plasminogen activator inhibitor-1 were measured using immunoblotting to assess coagulation and fibrinolysis. Human brain microvascular endothelial cells (HBMEC) were exposed to hypoxia with/without SARS-CoV-2 spike protein to mimic ischemic conditions and assessed for inflammation, RAAS balance, coagulation, and fibrinolysis. Our results showed that the SARS-CoV-2 spike protein caused an imbalance in the RAAS that increased the inflammatory signal and decreased the RAAS protective arm. SARS-CoV-2 spike protein increased coagulation and decreased fibrinolysis when coincident with ischemic insult, which was accompanied by a decrease in cerebral blood flow, an increase in neuronal death, and a decline in cognitive function. Losartan treatment restored RAAS balance and reduced spike protein-induced effects. SARS-CoV-2 spike protein exacerbates inflammation and hypercoagulation, leading to increased neurovascular damage and cognitive dysfunction. However, the AT1R blocker, Losartan, restored the RAAS balance and reduced COVID-19-induced thromboembolic cerebrovascular complications.
More Related Videos
08:41Live Imaging and Quantification of Viral Infection in K18 hACE2 Transgenic Mice Using Reporter-Expressing Recombinant SARS-CoV-2
Published on: November 5, 2021
06:39High-throughput Confocal Imaging of Quantum Dot-Conjugated SARS-CoV-2 Spike Trimers to Track Binding and Endocytosis in HEK293T Cells
Published on: April 21, 2022
